Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial

Frank Saran, Liam Welsh, Allan James, Catherine McBain, Rao Gattamaneni, Sarah Jefferies, Fiona Harris, Karine Pemberton, Jennifer Schaible, Shaun Bender, Agnieszka Cseh, Michael Brada, Frank Saran, Liam Welsh, Allan James, Catherine McBain, Rao Gattamaneni, Sarah Jefferies, Fiona Harris, Karine Pemberton, Jennifer Schaible, Shaun Bender, Agnieszka Cseh, Michael Brada

Abstract

Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM.

Methods: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment.

Results: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone.

Conclusions: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection.

Trial registration: NCT00977431 (first posted September 15, 2009).

Keywords: Afatinib; Dose-escalation; Glioblastoma; Radiotherapy; Temozolomide.

Conflict of interest statement

SJ reports having a private medical practice for CNS and Thyroid tumors, having an investment in Genesis Cancer Care at Newmarket within a Limited Company – Saunders and Jefferies Consultancy, and undertaking medicolegal work (one-two cases per year). KP declares being a Global project Manager working for Boehringer Ingelheim. JS declares employment with Boehringer Ingelheim Pharma GmbH & Co KG. SB declares employment with Boehringer Ingelheim Pharmaceuticals, Inc. AC declares employment with Boehringer Ingelheim International GmbH. All remaining authors declare no potential conflict of interest. The authors did not receive payment related to the development of the manuscript.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient disposition. a Regimen M: afatinib + TMZ + RT; b regimen U: afatinib + RT. AE adverse event, DLT dose-limiting toxicity, PD progressive disease, RT radiotherapy, TMZ temozolomide. *Due to trial completion, all patients are reported as having discontinued afatinib; however, one patient continued to receive afatinib outside of the clinical trial
Fig. 2
Fig. 2
Determination of the maximum tolerated dose based on the occurrence of dose limiting toxicities during the 6-week radiotherapy phase. MTD maximum tolerated dose, RT radiotherapy, TMZ temozolomide. *In Regimen M, one patient was replaced in the 20 mg afatinib group and one patient was replaced in the 40 mg afatinib group

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